Traditional treatment of cancer has been combinations of medicine (surgery), radiation and biochemical processes. In this context a major problem has been to differentiate between cancer cells and normal cells, that cancer cells have developed resistance against chemotherapy, in combination with critical location of tumours and/or metastases. An approach that has previously not been systematically used in the treatment of cancer is to utilise the differences in biophysical properties to selectively attack and destroy cancer cells, specifically by:                External mechanical stress and strain        Inducing apoptosis and/or necrosis        Traditional methods of treatment like chemotherapy/antioxidants in synergy with the use of acoustics        Combinations of the above stated procedures        
Related to externally induced mechanical stress, any body or systems of bodies, both physical and biological, has or can oscillate at various natural frequencies. Based on the significant differences in internal and external structure between cancer and normal cells, there are qualified reasons to believe that the mechanical resonance frequencies of normal cells and the equivalent for cancer cells are quite different.
A methodology for the application of resonance frequencies was first introduced in U.S. Pat. No. 4,315,514.
Apoptosis is a mechanism by which cells are programmed to die under a wide range of physiological, biochemical and developmental stimuli. From the perspective of cancer, apoptosis is both a mechanism which suppresses tumour genesis and is a predominant pathway in antineoplastic therapy. Many cancer cells circumvent the normal apoptotic mechanisms to prevent their self-destruction because of the many mutations they harbour. Thus, disarming apoptosis and other surveillance mechanisms is of fundamental significance in allowing the development of the malignant and metastatic phenotype of a cancer cell.
U.S. Pat. No. 5,984,882 describes a methodology for the treatment of cancer by inducing apoptosis with the use of ultrasonic energy.
The combination of ultrasound and chemotherapy are discussed in U.S. App. No. 20010007666 and U.S. App. Ser. No. 20010002251, which provide methodologies for the combination of various substances with ultrasonic sound for selective cell destruction.
Also, U.S. Pat. No. 6,308,714 describes a method for enhancing the action of anti-cancer agents with the combination of ultrasound.
Scientific evidence supporting the hypothesis of selective cell destruction by the combination of chemicals and ultrasound are provided in the literature. Wörle, Steinbach, Hofstädter (1994) [Cancer January;69(1)] studied the combined effects of high-energy shock waves and cytostatic drugs or cytokines on human bladder cancer cells. Maruyama et. al. (1999) [Anticancer Res May–June;19(3A)] studied the application of high energy shock waves to cancer treatment in combination with cisplatin and ATX-70 both in vitro and in vivo. Kato et. al. (2000) [Jpn J Cancer Res October;91(10)] investigated the mechanism of anti-tumour effect by the combination of bleomycin and shock waves. In this study they evaluated the synergistic effects on cancer cell proliferation and apoptosis in solid tumours.
The most compelling evidence of the effects of anti-cancer agents in combination with low-frequency ultrasound is provided by Nelson et. al. (2002) [Cancer Res December 15;62(24):7280–3]. They developed a novel drug delivery system that released drug from stabilized micelles upon application of low-frequency ultrasound and demonstrated efficacy using doxorubicin (Dox) to treat tumours in vivo. Forty-two BDIX rats were inoculated in each hind leg with a DHD/K12/TRb tumour cell line. Dox was encapsulated within stabilized Pluronic micelles and administered weekly i.v. to the rats starting 6 weeks after the tumour inoculations. One of the two tumours was exposed to low-frequency ultrasound for 1 h. Dox concentrations of 1.33, 2.67, and 8 mg/kg and ultrasound frequencies of 20 and 70 kHz were used for treatment. Application of low-frequency ultrasound (both 20 and 70 kHz) significantly reduced the tumor size when compared with noninsonated controls (P=0.0062) in the other leg for rats receiving encapsulated Dox. Significant tumour reduction was also noted for those rats receiving ultrasound and encapsulated Dox at 2.67 mg/kg (P=0.017) and rats receiving Dox and ultrasound at 70 kHz (P=0.029). They postulate that ultrasound releases the Dox from the micelles as they enter the insonated volume, and ultrasound could also assist the drug and/or carriers to extravasate and enter the tumour cells.
There may be a desire to bypass certain tissue or omitting the exposuring of specific organs, to locate or gain excess to, and/or target specific organs or cancerous tissue, or to treat tumours or metastatic tissue within or adjacent to body (air filled) cavities, with or without locally administered encapsulated cytostatica. In this respect a need for an endoscopic device for the (partial) treatment of cancer or cancerous tissue or organs with the use of acoustics is apparent.
Experiments
To provide evidence of selective cell destruction by acoustics, research were conducted with the use of balb/c nude mice with WiDr tumours transplanted on the right leg.
The aim of the experiments was to establish relevant frequencies where selective energy absorption occurred in malign tissue, and to conduct treatment at such frequencies on malign tumours.
With the use of an experimental set up as described in FIGS. 1, 2 and 3a, mice were placed in a cylindrical holder with one leg inserted into non-degassed water. Submerged hydrophones were placed on each side of the leg, with an acoustic transmitter located at one end of the tank.
To establish relevant frequencies where selective energy (pressure) absorption could be apparent, a spectroscopy study on five mice over a relatively wide frequency range was conducted. One mouse drowned during the experiments; causing the experiments to be finalized with four animals. The frequency range for the spectroscopy phase was from 9 kHz to 206 kHz, stepwise recording, based on the following frequency intervals:
TABLE 1Interval for stepwise recording.Range (kHz)Δf 8–25127–51254–753 79–1034108–1285134–1646171–2067Relevant data for the mice which were subjected to spectroscopy are provided in table 2. All numbers are in mm.
TABLE 2Relevant data for the mice subjected to spectroscopy.lbhdD1D2D310.24.95.42.619.24.621.49.05.87.22.516.24.924.29.97.67.52.625.04.125.510.66.15.32.823.65.022.9l = length of tumourb = width of tumourh = thickness of tumour including legd = diameter (thickness) of legD1 = Distance from holder to lower end of tumourD2 = Distance from lower end of tumour to toe tipD3 = Distance from holder to toe tip (healthy leg)
With continuous emission, voltage set at 70 V, exposure time 15 seconds at each frequency and ambient water temperature approx. 28.5 degrees C., Δp were measured over the leg with and without tumour (right leg vs. left leg) as a function of frequency.
As discussed in the chapter to follow concerning attenuation, the impedance of biological matter is inversely related to the water content of the material in question. Based on this analysis, the pressure drop for the healthy legs were expected to be larger than for legs with tumours. The experimental data were in accordance with this hypothesis.
Due to individual developments of the various tumours, their location on the legs varied. This again caused the proportion of the total leg which were submerged to vary for the different mice. To compensate for these effects, the pressure decrease over the legs were related to the length of the submerged leg.
FIG. 4 provides a graph of Δp divided by length of the submerged leg for the legs with tumours minus the equivalent for healthy legs.
Data showed significant selective (pressure) absorption at 27, 45, 72 and 91, all kHz, and to some extent 14 kHz.
Based on the results from the analysis of the spectroscopy data, actual treatment were conducted by the use of the following frequencies; 27 (group of 6 mice), 45 (group of 5 mice) and 91 (group of 6 mice), all kHz. Emission was continuous, voltage set at 80 V, exposure time 10 minutes, ambient water temperature approx. 28.5 degrees C.
An additional experiment on a group of 5 animals, exposed at 45 kHz for 10 minutes was conducted, but with pulsed emission. The pulse length was 2.22 ms, repetition rate 100 Hz, amplitude 20 V, voltage (peak to peak) 200 V. After the experiments, length (l), width (w) and height (h) of the tumours were measured every second day (one period), where the time of treatment is defined as period 0.
The volume of the tumours were calculated by the formula (l×w×h)π/6 (ellipsoidal approximation).
Due to the aggressive nature of the WiDr tumours, we had to start to eliminate mice after three periods.
TABLE 3aVariance analysis versus control-experiments one.GroupEst. αpEst. βp144.000.2287−34.79<0.00012−3.180.9159−6.440.3446343.790.2648−18.790.0592636.280.2908−29.350.0002
TABLE 3bActual model for the various treatment categories-experiments one.GroupEst. αpEst. βp193.490.003820.440.0027246.310.008748.79<0.0001393.290.007436.440.0041685.770.003625.880.0034Control49.490.175455.240.0005
Based on the data in FIG. 5a, a variance analysis was performed. The various groups were firstly analysed versus the control group, and secondly against itself. The data were analysed based on the equation:(Volume)group=α+β(treatment)group*(time)  (1)
As seen from table 3a, groups 1 (27 kHz) and 6 (45 kHz pulsed) provided significance against the control group.
Table 3b represents actual fits for the various groups.
Thermocouples were applied into the tumours for both spectroscopy and treatment, but no significant temperature increase (ΔT<0.1° C.) was apparent.
Due to significant wavelengths at these frequencies (5.6 cm at 27 kHz and 1.6 cm at 91 kHz), the problem of standing waves, and distance from the source (emitter) to the tumour is of great significance.
Total acoustic energy which was emitted was in the range of 3 W. Intensity at the source was 0.01 W/cm2, based on an area of the sphere of 277.6 cm2.
A second set of experiments were conducted with a slightly different set up, ref. FIG. 3b, with same type of mice, cancer line and tumour location.
The various treatment groups were:
Group 1
9 animals, f=27 kHz, applied voltage to the power amplifier=350 V peak to peak, I=2.2 A, exposure time=15 min.
Group 2
9 animals, f=91–95 kHz, Δf=1 kHz, applied voltage to the power amplifier=350 V peak to peak, I=1.1–1.4 A, exposure time=3 min. at each frequency.
Group 3
9 animals, f=31–35 kHz, Δf=1 kHz, applied voltage to the power amplifier=300 V peak to peak, I=2.6 A, exposure time=3 min. at each frequency.
Group 5
9 animals, f=13–17 kHz, Δf=1 kHz, applied voltage to the power amplifier=300 V peak to peak, I=0.5 A, exposure time=3 min. at each frequency.
Control, 16 animals.
Equivalent to experiment one, and based on the data in FIG. 5b, a variance analysis was performed. The various groups were firstly analysed versus the control group, and secondly against itself. The data were analysed based on the equation:(Volume)group=α+β1(treatment)group*(time)+β2(treatment)group*(time)^2  (2)
As seen from table 3c, group 1 (27 kHz) was the only group that provided significance against the control group.
Table 3d represents actual fits for the various groups.
TABLE 3cVariance analysis versus control-experiments two.GroupEst. αpEst. β1pEst. β2p1−66.390.050628.470.0114−4.330.00082−12.200.75267.570.5259−0.550.67723−10.420.79596.880.6443−1.190.47845−26.130.617915.670.2223−2.000.1431
TABLE 3dActual model for the various treatment categories-experiments two.GroupEst. αpEst. β1pEst. β2p14.580.812015.690.04152.450.0086258.780.0541−5.190.54966.23<0.0001360.550.0568−5.890.63705.580.0015544.850.33402.900.76614.780.0019Control70.980.0148−12.770.13136.78<0.0001
There are problems with acoustic impedance related to air, and subsequently the boundary layers between or within tissue or organs and air. In this respect the issue of tumours, metastases or cancerous tissue related to body cavities, or air within organs has to be addressed.
As mentioned, an answer to these challenges may be acoustic endoscopic procedures, devices and system, with or without the use of chemotherapeutic substances, which may or may not be encapsulated within therapeutic molecules. In the analysis to follow, we set the scene by firstly discussing the topic of attenuation. This is followed by a general discussion related to endoscopy and ultrasonic probes in particular, before new endoscopic techniques, apparatuses, method and system related to cancer treatment, are outlined.
Attenuation
The concept attenuation describes the total reduction in intensity (I) of an acoustic beam which propagates in a defined direction (x) within a medium.
Attenuation has its background in;                Absorption of energy in the medium        Deflection of energy due to reflection, refraction, diffraction and scatter.        
Absorption involves the transition of acoustic energy into a different energy form (heat). Reflection, refraction, diffraction and scatter causes the sound to transmit in different directions than the direction of propagation. While absorption is dependent on the state of the medium, deflection is both dependent on geometry and physical properties of the object. Reflection and refraction may occur at the boundary layer between regions with different impedance. In this context are the particle pressure, p, the particle velocity, v, related by the expression;p=ρcv  (3)where
ρ=density of the matter
c=speed of sound in the material
The expression p/v=Z=ρc, is called the characteristic impedance.
Diffraction may occur by a barrier or obstruction in the direction of propagation. Scatter is due to the structure of the material.
For a sound wave which propagates in x-direction in a specific type of tissue, the incremental intensity loss δI will be proportional with the intensity, I, and δx.
Subsequently we obtain;I(x)=I0e−μ(f)x  (4)where
I(x)=intensity at tissue depth x
I0=initial intensity
μ(f)=intensity absorption coefficient
Assuming that Attenuationabsorption>>Attenuationdeflection such that any deflection effects are neglected in the calculations to follow.
Attenuation is measured in neper (Np) or decibel (dB). It can be shown that 1 Np=8.886 dB.
μ (f) has subsequently the notation Np per unit of length (cm).
μ(f) relates to frequency by the expression;μ(f)=A(f/f1)m  (5)Combining equation (4) with the expression λ=c/f1, one obtains the absorption coefficient per unit of wave length;μλ=A(cfm−1)/f1m  (6)For soft tissue μ varies with frequency raised in the power of one, while for e.g. water it varies with the power of two.
By assuming m=1, equation (5) indicates that μλ can be independent of frequency.
FIG. 6 shows absorption, defined as α/f, where α=μ/2, as a function of frequency for various types of biological matter. Absorption for the different organs is to a large degree independent of frequency over large frequency ranges. For water it is apparent that attenuation effects first occur at significantly high frequencies (+5 MHz), and that a strong functional relationship to actual frequency is apparent at these frequencies.
Based on table (4) and equation (4) one can calculate the intensity absorption coefficients for various types of matter or tissue.
By studying table 4, it is clear that the absorption coefficient reduces with increasing water content of the tissue.
TABLE 4Parameters to calculate intensity absorption coefficients forvariuos types of tissue/matter. Basis forf1 = 1 MHz.Source: Duck (1990) [“Physical Properties of Tissue”,Academic Press, San Diego], Vlieger et. al. (1977)[“Handbook of Clinical Ultrasound”, John Wiley &Sons, New York].Type of tissue/matterA(Np/cm)mCranium2.31.7Muscle, human0.661.0along the fibersMuscle, human0.261.0normal to the fibersFat, human, stomach0.14–1.2(0.4)–1.4Blood0.0461.3Water0.000462.0Air (STP)2.32.0
In table 5 we have calculated the intensity loss at tissue debts of 0.5 cm and 0.25 cm for muscle mass with wave front both along and normal to the fibers at 100 kHz, 50 kHz, 25 kHz and 10 kHz.
As seen from the table, an absorption rate equivalent to 3.3% is evident at 100 kHz, tissue debt of 0.5 cm and wave front along the fibers. This is reduced to 0.1% at 10 kHz, tissue debt of 0.25 cm and wave front normal to the muscle fibers.
TABLE 5Intensity loss at tissue debts of 0.5 cm and 0.25 cm forhuman muscle tissue with wave front along and normalto the muscle fibers.100 kHz50 kHz25 kHz10 kHzI(0.5 cm)/I0Along the fibers0.9670.9830.9910.996Normal to the fibers0.9870.9930.9960.998I(0.25 cm)/I0Along the fibers0.9830.9910.9950.998Normal to the fibers0.9930.9960.9980.999
The above stated theoretical analysis, which indicates low intensity losses due to absorption for the frequencies in question, supports the empirical findings of the lack of temperature increase, even though there are additional complicating factors like conductivity to ambient water, heat transfer due to blood supply etc.
Also, the reversed effect may be apparent, that the acoustic energy may be trapped within a body, due to its insulation by air.
Endoscopy in General
Endoscopy is a well established medical procedure for both diagnosis and treatment within body cavities. The procedure uses a flexible lighted tube with a lens or video camera on the end, with the additional possibility of an instrument channel for the use of tools to cut, burn, apply various needles, and the like. If a camera is used it is connected to a display unit for viewing.
For upper endoscopy the tube is passed through the mouth to view the esophagus, stomach and the first part of the bowel.
A colonoscope is a type of endoscope that is inserted through the anus, the rectum and into the colon. Colonoscopy allows the therapist to see the lining of the entire colon.
The combination of the ultrasound probe and an endoscope have led to the development of echoendoscopes. Endoscopic ultrasound combines an ultrasound processor on the tip of an endoscope, allowing for improved ultrasound imaging of the gastrointestinal tract and the abdominal organs adjacent to it. These instruments allow for the examination of both the lining of the digestive tract with the endoscope, in addition to the wall of the tract and its surrounding structures such as the liver, pancreas, bile ducts, and lymph nodes.
It is also possible to study the flow of blood in vessels by Doppler ultrasound. Also, to pass a small needle down the endoscope and direct it, under ultrasound guidance, into structures within or adjacent to the digestive tract, such as lymph nodes or suspicious tissue, can be performed. In this way, tissue can be aspirated for analysis by a pathologist. This technique is known as fine needle aspiration (FNA).
Small flexible catheters have been developed that can be passed through a regular endoscope. They are referred to as “miniprobes” or “catheter probes”. They provide high frequency ultrasound images, often in the 12–30 MHz range, while standard diagnostic ultrasound are performed in the 3 MHz–8 MHz range, which allow for very detailed images of e.g. the wall of the gastrointestinal tract.
Echoendoscope procedures can provide a variety of information. It is primarily used to detect suspected cancers or to evaluate how far a previously diagnosed cancer has spread in order to determine the appropriate therapy. Echoendoscopy is also used to stage cancers of the esophagus, stomach, pancreas, and rectum. Spread to adjacent lymph nodes and blood vessels can be determined by the imaging and fine-needle aspiration capabilities of echoendoscope. Echoeindoscope gives partial, but incomplete, information regarding the spread of these tumours to adjacent organs due to its limited depth of penetration. However, imaging enhancements may allow for greater evaluation of adjacent organs.
More recent applications have been to evaluate patients with fecal incontinence. stage lung cancers, and to evaluate for clots in the vessels of the abdomen with the use of Doppler.
If a fluid collection is seen, it can be suctioned through the scope and the fluid sent for analysis. Occasionally, if there is a cyst that needs drainage, a cyst-gastrostomy or a cyst-duodenostomy may be performed, by placing a stent through the stomach or small bowel into the cyst.
For patients with pancreatic cancer and severe pain, a celiac-plexus blockade can be performed in which medications will be injected into the nerves responsible for transmitting this pain. This can lessen the pain in these patients for a period of up to several months.
Further Prior Art
Ultrasonic probes which can be introduced into a body are well known. E.g. U.S. Pat. No. 4,561,446 describes a probe tube which an ultrasonic array is disposed. The primary aim of the device is the employment for bladder endoscopy of male patients. The system comprises an optical insert and an ultrasonic array which are disposed in two layers radially offset and also offset relative to one another in the longitudinal direction of the tube.
Also, U.S. Pat. No. 5,176,142 describes an endoscopic ultrasound probe which has a rotatable transducer array for obtaining two-dimensional cross-sectional images of a subject along a variety of scan planes. The probe also has a take-up mechanism comprising a flexible cable assembly which is electrically connected to an array for remote ultrasound imaging system. U.S. Pat. No. 5,320,104 is quite similar to U.S. Pat. No. 5,176,142, but it represents an endoscopic ultrasound probe specifically for use in transesophageal echo cardiography comprising a rotatable ultrasound transducer array for obtaining two-dimensional cross-sectional images. Among other related technologies. U.S. Pat. No. 5,967,968 describes an endoscopic imaging system for viewing an object within a patient's body cavity including an endoscope for viewing an image of the object. The endoscope comprising a distal end, an instrument channel, and a probe to determine the size of an object. U.S. Pat. No. 6,315,712 comprises a video endoscopic probe which has a distal terminal, utilizing an objective, a colour CCD (charge-couple device) sensor, and an electrical interface microcircuit. The probe utilizes a continuous bundle of optical fibers which is coupled to a light source.
Objects and Summary of the Invention
An object of the present invention is to provide a probe, a method and a system for treating cancer in a patient, preferably a human, alternatively an animal patient.
A further object of the present invention is to provide a probe, a method and a system for destroying tumours or cancerous cells and tissue, with or without the combination of encapsulated cytostatica.
A further object of the present invention is to provide a probe, a method and a system for treating cancerous tissue, which is less detrimental to the patient than prior art methods.
Further objects of the present invention will be apparent from the above background of the invention in conjunction with the following detailed description of the invention.
The objects stated above, as well as further advantages and favorable results, are achieved by means of a probe, a method and a system as set forth in the appended set of claims.